The present invention relates to solid pharmaceutical formulations whereby, upon oral administration, the active ingredients are released with a slow, zero order selectable rate.
Various techniques are known for formulating active ingredients to selectively control the resultant release rate of the drug, e.g., via sustained release, slow release, fast release, etc.
It is important for any pharmaceutical formulation technique to provide the capability of preselecting a desired release rate which can be tailored to the unique characteristics of each drug. For example, many formulations exist which permit selection of very slow release rates, i.e., sustained release formulations. (See, e.g., U.S. Pat. No. 3,641,236 based upon glycerol fatty acid esters and U.S. Pat. No. 3,950,508 based upon alkyl celluloses and inert powders such as talc, which, in combination with other ingredients, produce a gradual disaggregation of the sustained release tablet.) These can often cause toxicity and other side effects due to an inordinately long presence of the drug in the body. Thus, methods of preselecting somewhat faster release rates, i.e., slow release rates--midway between fast and sustained rates--are needed.
Moreover, as Zaffaroni has suggested (Therapeutic Implications of Controlled Drug Delivery, Future Trends in Therapeutics, Ed. F. C. McMahon, Mount Kisco, N.Y., Futura Publishing, 1978, pp. 143-160), an ideal drug delivery system would allow a constant amount of drug to be absorbed per unit of time (zero-order kinetics). Thus, serum concentrations would not fluctuate under steady-state conditions. Weinberger et. al., The New England Journal of Medicine, Vol. 299, No. 16, Oct. 19, 1978, pp. 852-857, have stated: "Modern technology related to controlled oral delivery systems should be applied to theophylline in an attempt to approximate zero-order absorption so that the continuous stabilizing effect of this drug on the airways can be maintained in the most effective, convenient and risk-free manner." Similar sentiments have been echoed by many pharmaceutical researchers in recognizing the preference for and importance of zero order release rates. See, e.g., U.S. Pat. No. 3,965,255. Nevertheless, zero order release has rarely been achieved; there is no available technique by which a selected drug can be systematically formulated to provide zero order release kinetics in vitro or in vivo.
Furthermore, many formulations result in a bioavailability curve having a high concentration peak at the beginning of release with a subsequent tailing off at longer times (see, e.g., curve ( ) of FIG. 1). Such concentration peaks are generally undesirable since they can lead to toxicity and/or other adverse side effects. Additionally, they significantly limit the freedom to increase the unit dosage of administration. Such an increased dosage would correspondingly increase the peak concentration. Under such circumstances, it is not possible to decrease the frequency of administration by increasing the unit dosage. This is a significant disadvantage in view of the well established correlation between the likelihood that a patient will fail to take doses of his medication and the required frequency of administration. Zero order release would attenuate this adverse effect by regulating the amount of active ingredient released in vivo per unit of time.
As can be seen, in most instances, it is desirable to achieve a relatively slow, zero order release rate of medication. This precise rate should be easily selectable so that the resultant in vivo absorption is desirably controlled and the bioavailability of the drug is maximized.